Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors.
Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors.
复制标题
DOI：
10.1085/jgp.202213300
复制
发表时间：
2023-05-01
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
细胞内成纤维细胞生长因子（iFGF）调节电压门控钠（NaV）通道表达和门控。使用小鼠模型和异源表达在非洲爪蟾卵母细胞，我们描述了iFGF如何改变NaV通道激活和失活的机制。电压门控钠（NaV）通道负责动作电位的起始和传播。在心脏中，主要的NaV1.5 α亚基由四个同源重复序列（I-IV）组成，并与多种辅助蛋白（包括细胞内成纤维细胞生长因子（iFGF））形成大分子复合物。尽管具有高同源性，iFGF、iFGF 11-iFGF 14以及单独的iFGF剪接变体中的每一种都差异性地调节NaV通道门控，并且这些差异效应的机制仍然难以捉摸。在小鼠和大鼠心室肌细胞中进行了许多探索NaV1.5的iFGF调节的工作，其中iFGF 13 VY是主要表达的iFGF，而缺乏对人心脏主导的iFGF 12 B对NaV1.5调节的研究。在这项研究中，我们使用心脏特异性Fgf 13缺失的小鼠模型来研究iFGF 13 VY和iFGF 12 B表达的后果。我们观察到不同的影响的电压依赖性的激活和失活的钠电流（INa），以及峰值INa衰减的动力学。天然肌细胞中的结果与在非洲爪蟾卵母细胞中异源表达的人NaV1.5重复，并且使用电压钳荧光测定法（VCF）的额外实验揭示了iFGF对重复IV（VSD-IV）中NaV1.5电压传感器结构域的激活的特异性作用。iFGF嵌合体进一步揭示了所有三个iFGF结构域的作用（即，N-末端、核心和C-末端）对VSD-IV的调节，以及较慢的失活时间域。我们在这里提出了一种新的iFGF调节机制，该机制对单个iFGF亚型具有特异性，并对NaV通道/电流动力学产生不同的功能效应。
Intracellular fibroblast growth factors (iFGF) regulate voltage-gated sodium (NaV) channel expression and gating. Using a mouse model and heterologous expression in Xenopus oocytes, we describe mechanisms of how iFGF alters NaV channel activation and inactivation. Voltage-gated sodium (NaV) channels are responsible for the initiation and propagation of action potentials. In the heart, the predominant NaV1.5 α subunit is composed of four homologous repeats (I–IV) and forms a macromolecular complex with multiple accessory proteins, including intracellular fibroblast growth factors (iFGF). In spite of high homology, each of the iFGFs, iFGF11–iFGF14, as well as the individual iFGF splice variants, differentially regulates NaV channel gating, and the mechanisms underlying these differential effects remain elusive. Much of the work exploring iFGF regulation of NaV1.5 has been performed in mouse and rat ventricular myocytes in which iFGF13VY is the predominant iFGF expressed, whereas investigation into NaV1.5 regulation by the human heart-dominant iFGF12B is lacking. In this study, we used a mouse model with cardiac-specific Fgf13 deletion to study the consequences of iFGF13VY and iFGF12B expression. We observed distinct effects on the voltage-dependences of activation and inactivation of the sodium currents (INa), as well as on the kinetics of peak INa decay. Results in native myocytes were recapitulated with human NaV1.5 heterologously expressed in Xenopus oocytes, and additional experiments using voltage-clamp fluorometry (VCF) revealed iFGF-specific effects on the activation of the NaV1.5 voltage sensor domain in repeat IV (VSD-IV). iFGF chimeras further unveiled roles for all three iFGF domains (i.e., the N-terminus, core, and C-terminus) on the regulation of VSD-IV, and a slower time domain of inactivation. We present here a novel mechanism of iFGF regulation that is specific to individual iFGF isoforms and that leads to distinct functional effects on NaV channel/current kinetics.
登录
查看更多内容
影响因子：
4.6
作者：
Ton AT;Nguyen W;Sweat K;Miron Y;Hernandez E;Wong T;Geft V;Macias A;Espinoza A;Truong K;Rasoul L;Stafford A;Cotta T;Mai C;Indersmitten T;Page G;Miller PE;Ghetti A;Abi-Gerges N
通讯作者：
Abi-Gerges N
DOI：
10.1007/s00424-016-1911-9
发表时间：
2017-02
期刊：
Pflugers Archiv : European journal of physiology
影响因子：
--
作者：
Barbosa C;Xiao Y;Johnson AJ;Xie W;Strong JA;Zhang JM;Cummins TR
通讯作者：
Cummins TR
影响因子：
16.2
作者：
CHAHINE, M;GEORGE, AL;HORN, R
通讯作者：
HORN, R
影响因子：
8
作者：
Zhu W;Wang W;Angsutararux P;Mellor RL;Isom LL;Nerbonne JM;Silva JR
通讯作者：
Silva JR
影响因子：
5.5
作者：
Brunet, S;Aimond, F;Nerbonne, JM
通讯作者：
Nerbonne, JM